Shuxia Yao

Sex-dependent neural effect of oxytocin during subliminal processing of negative emotion faces

&NA; In line with animal models indicating sexually dimorphic effects of oxytocin (OXT) on social‐emotional processing, a growing number of OXT‐administration studies in humans have also reported sex‐dependent effects during social information processing. To explore whether sex‐dependent effects already occur during early, subliminal, processing stages the present pharmacological fMRI‐study combined the intranasal‐application of either OXT or placebo (n = 86–43 males) with a backward‐masking emotional face paradigm. Results showed that while OXT suppressed inferior frontal gyrus, dorsal anterior cingulate and anterior insula responses to threatening face stimuli in men it increased them in women. In women increased anterior cingulate reactivity during subliminal threat processing was also positively associated with trait anxiety. On the network level, sex‐dependent effects were observed on amygdala, anterior cingulate and inferior frontal gyrus functional connectivity that were mainly driven by reduced coupling in women following OXT. Our findings demonstrate that OXT produces sex‐dependent effects even at the early stages of social‐emotional processing, and suggest that while it attenuates neural responses to threatening social stimuli in men it increases them in women. Thus in a therapeutic context OXT may potentially produce different effects on anxiety disorders in men and women. HighlightsOxytocin (OXT) induced sex‐dependent effect on BOLD level and functional connectivity.OXT decreased neural responses to negative faces in men but increased them in women.Increased ACC activity after OXT was positively linked with trait anxiety in women.OXT decreased functional connectivity in women.Sex might be an important factor moderating the putative anxiolytic effects of OXT.

Voluntary control of anterior insula and its functional connections is feedback-independent and increases pain empathy.

Real-time functional magnetic resonance imaging (rtfMRI)-assisted neurofeedback (NF) training allows subjects to acquire volitional control over regional brain activity. Emerging evidence suggests its potential clinical utility as an effective non-invasive treatment approach in mental disorders. The therapeutic potential of rtfMRI-NF training depends critically upon whether: (1) acquired self-regulation produces functionally relevant changes at behavioral and brain network levels and (2) training effects can be maintained in the absence of feedback. To address these key questions, the present study combined rtfMRI-NF training for acquiring volitional anterior insula (AI) regulation with a sham-controlled between-subject design. The functional relevance of acquired AI control was assessed using both behavioral (pain empathy) and neural (activity, functional connectivity) indices. Maintenance of training effects in the absence of feedback was assessed two days later. During successful acquisition of volitional AI up-regulation subjects exhibited stronger empathic responses, increased AI-prefrontal coupling in circuits involved in learning and emotion regulation and increased resting state connectivity within AI-centered empathy networks. At follow-up both self-regulation and increased connectivity in empathy networks were fully maintained, although without further increases in empathy ratings. Overall these findings support the potential clinical application of rtfMRI-NF for inducing functionally relevant and lasting changes in emotional brain circuitry.

Oxytocin Modulates Attention Switching Between Interoceptive Signals and External Social Cues

Emotional experience involves an integrated interplay between processing of external emotional cues and interoceptive feedback, and this is impaired in a number of emotional disorders. The neuropeptide oxytocin (OT) enhances the salience of external social cues but its influence on interoception is unknown. The present pharmaco-fMRI study therefore investigated whether OT enhances interoceptive awareness and if it influences the interplay between interoceptive and salience processing. In a randomized, double-blind, between-subject, design study 83 subjects received either intranasal OT or placebo. In Experiment 1, subjects performed a heartbeat detection task alone, while in Experiment 2 they did so while viewing both neutral and emotional face stimuli. Interoceptive accuracy and neural responses in interoceptive and salience networks were measured. In Experiment 1, OT had no significant influence on interoceptive accuracy or associated activity in the right anterior insula (AI) and dorsal anterior cingulate cortex. However, in Experiment 2 when face stimuli were also presented, OT decreased interoceptive accuracy and increased right AI activation and its functional connectivity with the left posterior insula (PI), with the latter both being negatively correlated with accuracy scores. The present study provides the first evidence that while OT does not influence processing of interoceptive cues per se it may switch attention away from them towards external salient social cues by enhancing right AI responses and its control over the PI. Thus OT may help regulate the interplay between interoceptive and external salience processing within the insula and could be of potential therapeutic benefit for emotional disorders.

Oxytocin biases men but not women to restore social connections with individuals who socially exclude them

We normally react to individuals who exclude us socially by either avoiding them or increasing our attempts to interact with them. The neuropeptide oxytocin can promote social bonds and reduce social conflict and we therefore investigated whether it facilitates more positive social responses towards individuals who exclude or include us. In a double-blind, placebo-controlled, between-subject design 77 healthy Chinese male and female participants received intranasal oxytocin (40 IU) or placebo before playing a modified virtual ball-tossing game with three fictitious partners who either showed exclusion, inclusion or neutral behavioral interactions with them. Results showed that both male and female subjects threw the ball more often to individuals who excluded rather than included them, although oxytocin did not alter this or awareness/feelings of exclusion or inclusion. However, when subjects returned a week later males, but not females, in the oxytocin group exhibited an increased liking for, and preference for playing again with, players who had previously excluded them. This oxytocin effect was positively associated with independent traits. Our findings suggest that in a collectivist culture oxytocin may promote the desire of males, but not females, with a stronger independent orientation to rebuild social connections with individuals who have previously excluded them.

Oxytocin Increases the Perceived Value of Both Self- and Other-Owned Items and Alters Medial Prefrontal Cortex Activity in an Endowment Task

The neuropeptide oxytocin (OXT) can influence self-processing and may help motivate us to value the attributes of others in a more self-like manner by reducing medial prefrontal cortex (mPFC) responses. We do not know however whether this OXT effect extends to possessions. We tend to place a higher monetary value on specific objects that belong to us compared to others, known as the “endowment effect”. In two double-blind, between-subject placebo (PLC) controlled experiments in subjects from a collectivist culture, we investigated the influence of intranasal OXT on the endowment effect, with the second study incorporating functional magnetic resonance imaging (fMRI). In the task, subjects decided whether to buy or sell their own or others’ (mother/father/classmate/stranger) possessions at various prices. Both experiments demonstrated an endowment effect in the self-owned condition which extended to close others (mother/father) and OXT increased this for self and all other-owned items. This OXT effect was associated with reduced activity in the ventral mPFC (vmPFC) in the self-owned condition but increased in the mother-condition. For the classmate- and stranger-owned conditions OXT increased activity in the dorsal mPFC (dmPFC). Changes in vmPFC activation were associated with the size of the endowment effect for self- and mother-owned items. Functional connectivity between the dmPFC and ventral striatum (VStr) was reduced by OXT in self- and mother-owned conditions and between vmPFC and precuneus in the self-condition. Overall our results show that OXT enhances the endowment effect for both self- and other-owned items in Chinese subjects. This effect is associated with reduced mPFC activation in the self-condition but enhanced activation in all other-conditions and involves differential actions on both dorsal and ventral regions as well as functional connectivity with brain reward and other self-processing regions. Overall our findings suggest that OXT increases the perceived value of both self- and other-owned items by acting on neural circuitry involved in self-processing and reward.

Oxytocin Enhancement of Emotional Empathy: Generalization Across Cultures and Effects on Amygdala Activity

Accumulating evidence suggests that the neuropeptide oxytocin (OXT) can enhance empathy although it is unclear which specific behavioral and neural aspects are influenced, and whether the effects are modulated by culture, sex, and trait autism. Based on previous findings in Caucasian men, we hypothesized that a single intranasal dose of OXT would specifically enhance emotional empathy (EE) via modulatory effects on the amygdala in an Asian (Chinese) population and explored the modulatory role of sex and trait autism on the effects. We first conducted a double-blind, randomized between-subject design experiment using a modified version of the multifaceted empathy task to determine whether OXT’s facilitation of EE can be replicated in Chinese men (n = 60). To further explore neural mechanisms behind and potential sex differences, functional MRI and skin conductance measures were acquired in an independent experiment incorporating men and women (n = 72). OXT enhanced EE across experiments and sex, an effect that was accompanied by reduced amygdala activity and increased skin conductance responses. On the network level OXT enhanced functional coupling of the right amygdala with the insula and posterior cingulate cortex for positive valence stimuli but attenuated coupling for negative valence stimuli. The effect of OXT on amygdala functional connectivity with the insula was modulated by trait autism. Overall, our findings provide further support for the role of OXT in facilitating EE and demonstrate that effects are independent of culture and sex and involve modulatory effects on the amygdala and its interactions with other key empathy regions.

Oxytocin Facilitates Approach Behavior to Positive Social Stimuli via Decreasing Anterior Insula Activity

Abstract Background The neuropeptide oxytocin can extensively modulate human social behavior and affective processing, and its effects can be interpreted in terms of mediating approach-avoidance motivational processes. However, little is known about how oxytocin mediates approach-avoidance behavior and particularly the underlying neural mechanisms. Methods In a randomized, double-blind, between-subject design, the present pharmaco-fMRI study used an approach-avoidance paradigm to investigate oxytocin’s effects on approach-avoidance behavior and associated neural mechanisms. Results Results revealed that oxytocin generally decreased activity in the right striatum irrespective of response (approach/avoidance) and social context, suggesting an inhibitory effect on motivational representation during both appetitive approach and aversive avoidance. Importantly, while on the behavioral level oxytocin selectively enhanced accuracy when approaching social positive stimuli, on the neural level it decreased left ventral and right dorsal anterior insula activity in response to social vs nonsocial positive stimuli compared with the placebo treatment. The left ventral anterior insula activity was negatively correlated with the corresponding accuracy difference scores in the oxytocin but not in the placebo group. Conclusion Given the role of the ventral anterior insula in emotional processing and the dorsal anterior insula in salience processing, the oxytocin-induced suppression of activity in these regions may indicate that oxytocin is acting to reduce interference from hyper-activity in core regions of the emotional and salience networks when approaching salient positive social stimuli and thereby to promote social interaction. Thus, oxytocin may be of potential therapeutic benefit for psychiatric disorders exhibiting avoidance of social stimuli.

Can pharmacological enhancement of the placebo effect be a novel therapy for working memory impairments

Working memory is considered as a core aspect of cognitive function and its impairment in a wide range of mental disorders has resulted in it being considered as an important transdiagnostic feature. To date pharmacological and behavioural strategies for augmenting working memory have achieved only moderate success. Here we have taken a different approach by combining expectancy effects with intranasal oxytocin as an adjunct given previous evidence that it may enhance placebo effects. In a randomised controlled clinical trial we demonstrate that while working memory performance is not influenced by expectancy per se when it is given in conjunction with oxytocin performance in terms of accuracy can be significantly enhanced following positive expectancy induction (placebo effect) and impaired following negative expectancy induction (nocebo effect). Thus combining expectancy effects with intranasal oxytocin may represent a radical new approach for improving working memory function in mental disorders.

Attentional set to safety recruits the medial prefrontal cortex

During threat assessment, the early detection of danger is highly adaptive, yet the fast orientation towards safety is also key to survival. The present study aimed to explore how the human brain searches for safety by manipulating subjects’ attentional set to cues associated with shock probability. Subjects were asked to judge random dots motion (RDM) direction and could be shocked for incorrect responses (RDM task) while keeping alert in detecting the shock probability cues (cue detection task). In contrast to the safe condition, where subjects searched for cues associated with no shock probability, incorrect responses to ‘dangerous+’ (D+) cues would increase the shock probability and correct responses to ‘dangerous-’ (D-) cues would decrease shock probability. In the RDM task, results showed that relative to the D+, the safe attentional set resulted in stronger activation in the ventral medial prefrontal cortex (vmPFC), a core region involved in flexible threat assessment and safety signalling. The vmPFC was also recruited by the D-compared to the D + attentional set. In the cue detection task, shorter response times and greater accuracy were observed for D+ compared to D‐ and safe cues. Correspondingly, at the neural level D+ cues induced increased activity in the frontoparietal attention network including the inferior parietal lobule and intraparietal sulcus. Overall, our findings demonstrate that attentional set for searching safety recruits the vmPFC, while detection of threat elicits activity in the frontoparietal attention network, suggesting a new role for these regions in human defensive survival circuitry. Significance Statement While early detection of threat is highly adaptive, the fast orientation towards safety is also key to survival. However, little is known about neural mechanisms underlying attentional set to safety. Using a novel dots motion paradigm combined with fMRI, we explored how human brain prepares for safety searching by manipulating subjects’ attentional set to cues associated with shock probability. Relative to the dangerous attentional set associated with increasing shock probability, the safe attentional set resulted in stronger activity in the ventral medial prefrontal cortex, a core region involved in flexible threat assessment and safety signalling, suggesting a new role for this region in human defensive survival system in encoding stimuli with survival significance.

Real-time functional connectivity-based neurofeedback of amygdala-frontal pathways reduces anxiety

Deficient emotion regulation and exaggerated anxiety represent a major transdiagnostic psychopathological marker. On the neural level these deficits have been closely linked to impaired, yet treatment-sensitive, prefrontal regulatory control over the amygdala. Gaining direct control over these pathways could therefore provide an innovative and promising strategy to regulate exaggerated anxiety. To this end the current proof-of-concept study evaluated the feasibility, functional relevance and maintenance of a novel connectivity-informed real-time fMRI neurofeedback training. In a randomized within-subject sham-controlled design high anxious subjects (n = 26) underwent real-time fMRI-guided training to enhance connectivity between the ventrolateral prefrontal cortex (vlPFC) and the amygdala (target pathway) during threat exposure. Maintenance of regulatory control was assessed after three days and in the absence of feedback. Training-induced changes in functional connectivity of the target pathway and anxiety ratings served as primary outcomes. Training of the target, yet not the sham-control, pathway significantly increased amygdala-vlPFC connectivity and decreased subjective anxiety levels. On the individual level stronger connectivity increases were significantly associated with anxiety reduction. At follow-up, volitional control over the target pathway and decreased anxiety level were maintained in the absence of feedback. The present results demonstrate for the first time that successful self-regulation of amygdala-prefrontal top-down regulatory circuits may represent a novel strategy to control anxiety. As such, the present findings underscore both the critical contribution of amygdala-prefrontal circuits to emotion regulation and the therapeutic potential of connectivity-informed real-time neurofeedback.